rs121918616

chr1-160130283-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000702.4(ATP1A2):c.1643G>A(p.Arg548His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R548C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATP1A2 NM_000702.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.75

Genes affected

ATP1A2 (HGNC:800): (ATPase Na+/K+ transporting subunit alpha 2) The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The catalytic subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes an alpha 2 subunit. Mutations in this gene result in familial basilar or hemiplegic migraines, and in a rare syndrome known as alternating hemiplegia of childhood. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-160130282-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 871961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, ATP1A2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 1-160130283-G-A is Pathogenic according to our data. Variant chr1-160130283-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160130283-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-160130283-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A2	NM_000702.4	c.1643G>A	p.Arg548His	missense_variant	12/23	ENST00000361216.8
ATP1A2	XM_047421286.1	c.752G>A	p.Arg251His	missense_variant	5/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A2	ENST00000361216.8	c.1643G>A	p.Arg548His	missense_variant	12/23	1	NM_000702.4	P1
ATP1A2	ENST00000392233.7	c.1643G>A	p.Arg548His	missense_variant	12/23	5
ATP1A2	ENST00000447527.1	c.776G>A	p.Arg259His	missense_variant	5/16	2
ATP1A2	ENST00000472488.5	n.1746G>A		non_coding_transcript_exon_variant	12/20	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251212 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Migraine, familial basilar Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 13, 2005

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 25, 2020

Published in vitro functional studies demonstrated that R548H variant results in reduced ATPase activity, alters the affinity for sodium and potassium, and reduces catalytic turnover compared to the wild type protein (Swarts et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18498390, 23954377, 16088919, 16344534, 27445835) -

ATP1A2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant has been previously reported as a heterozygous change in patients with Hemiplegic migraine and Basilar migraine (PMID: 16344534, and Maksemous et al., 2019). Additionally, a different variant at the same amino acid position (p.Arg548Cys) has been seen in multiple patients with ATP1A2-Related Disorders (ClinVar Variation ID: 871961). In vitro overexpression studies revealed that the c.1643G>A (p.Arg548His) variant has reduced Na(+) affinity and increased K(+) affinity, leading to reduced catalytic turnover compared to the wild type protein (PMID: 23954377). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/251212) and thus is presumed to be rare. The c.1643G>A (p.Arg548His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1643G>A (p.Arg548His) variant is classified as Pathogenic. -

Migraine, familial hemiplegic, 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Nov 16, 2023

Criteria applied: PS4_MOD,PM5,PS3_SUP,PM2_SUP,PP1,PP2,PP3 -

Familial hemiplegic migraine Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 12, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg548 amino acid residue in ATP1A2. Other variant(s) that disrupt this residue have been observed in individuals with ATP1A2-related conditions (PMID: 18498390), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects ATP1A2 function (PMID: 23954377). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP1A2 protein function. ClinVar contains an entry for this variant (Variation ID: 12926). This missense change has been observed in individuals with clinical features of autosomal dominant ATP1A2-related conditions (PMID: 16344534; Invitae; Maksemous et al. 2019 Cephalagia Reports Vol. 2). This variant is present in population databases (rs121918616, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 548 of the ATP1A2 protein (p.Arg548His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	4.2	H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.1	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.97		Gain of catalytic residue at L550 (P = 0.0544);Gain of catalytic residue at L550 (P = 0.0544);
MVP		0.98
MPC		2.0
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.68
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918616; hg19: chr1-160100073;